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Title: Functional assessment of human enhancer activities using whole-genome STARR-sequencing

Abstract

Background: Genome-wide quantification of enhancer activity in the human genome has proven to be a challenging problem. Recent efforts have led to the development of powerful tools for enhancer quantification. However, because of genome size and complexity, these tools have yet to be applied to the whole human genome. Results: In the current study, we use a human prostate cancer cell line, LNCaP as a model to perform whole human genome STARR-seq (WHG-STARR-seq) to reliably obtain an assessment of enhancer activity. This approach builds upon previously developed STARR-seq in the fly genome and CapSTARR-seq techniques in targeted human genomic regions. With an improved library preparation strategy, our approach greatly increases the library complexity per unit of starting material, which makes it feasible and cost-effective to explore the landscape of regulatory activity in the much larger human genome. In addition to our ability to identify active, accessible enhancers located in open chromatin regions, we can also detect sequences with the potential for enhancer activity that are located in inaccessible, closed chromatin regions. When treated with the histone deacetylase inhibitor, Trichostatin A, genes nearby this latter class of enhancers are up-regulated, demonstrating the potential for endogenous functionality of these regulatory elements. Inmore » conclusion, WHG-STARR-seq provides an improved approach to current pipelines for analysis of high complexity genomes to gain a better understanding of the intricacies of transcriptional regulation.« less

Authors:
 [1];  [1];  [1];  [1];  [2];  [3]
  1. Univ. of Chicago, IL (United States). Inst. for Genomics and Systems Biology; Argonne National Lab. (ANL), Argonne, IL (United States); Univ. of Chicago, IL (United States). Dept. of Human Genetics
  2. Univ. of Chicago, IL (United States). Dept. of Human Genetics
  3. Univ. of Chicago, IL (United States). Inst. for Genomics and Systems Biology; Argonne National Lab. (ANL), Argonne, IL (United States); Univ. of Chicago, IL (United States). Dept. of Human Genetics; Tempus Labs, Chicago, IL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH). National Human Genome Research Institute (NHGRI); USDOE
OSTI Identifier:
1467453
Grant/Contract Number:  
AC02-06CH11357; U54HG006996
Resource Type:
Accepted Manuscript
Journal Name:
Genome Biology (Online)
Additional Journal Information:
Journal Name: Genome Biology (Online); Journal Volume: 18; Journal Issue: 1; Journal ID: ISSN 1474-760X
Publisher:
BioMed Central
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; STARR-seq; enhancers; non-coding regions; regulatory elements

Citation Formats

Liu, Yuwen, Yu, Shan, Dhiman, Vineet K., Brunetti, Tonya, Eckart, Heather, and White, Kevin P. Functional assessment of human enhancer activities using whole-genome STARR-sequencing. United States: N. p., 2017. Web. doi:10.1186/s13059-017-1345-5.
Liu, Yuwen, Yu, Shan, Dhiman, Vineet K., Brunetti, Tonya, Eckart, Heather, & White, Kevin P. Functional assessment of human enhancer activities using whole-genome STARR-sequencing. United States. doi:10.1186/s13059-017-1345-5.
Liu, Yuwen, Yu, Shan, Dhiman, Vineet K., Brunetti, Tonya, Eckart, Heather, and White, Kevin P. Mon . "Functional assessment of human enhancer activities using whole-genome STARR-sequencing". United States. doi:10.1186/s13059-017-1345-5. https://www.osti.gov/servlets/purl/1467453.
@article{osti_1467453,
title = {Functional assessment of human enhancer activities using whole-genome STARR-sequencing},
author = {Liu, Yuwen and Yu, Shan and Dhiman, Vineet K. and Brunetti, Tonya and Eckart, Heather and White, Kevin P.},
abstractNote = {Background: Genome-wide quantification of enhancer activity in the human genome has proven to be a challenging problem. Recent efforts have led to the development of powerful tools for enhancer quantification. However, because of genome size and complexity, these tools have yet to be applied to the whole human genome. Results: In the current study, we use a human prostate cancer cell line, LNCaP as a model to perform whole human genome STARR-seq (WHG-STARR-seq) to reliably obtain an assessment of enhancer activity. This approach builds upon previously developed STARR-seq in the fly genome and CapSTARR-seq techniques in targeted human genomic regions. With an improved library preparation strategy, our approach greatly increases the library complexity per unit of starting material, which makes it feasible and cost-effective to explore the landscape of regulatory activity in the much larger human genome. In addition to our ability to identify active, accessible enhancers located in open chromatin regions, we can also detect sequences with the potential for enhancer activity that are located in inaccessible, closed chromatin regions. When treated with the histone deacetylase inhibitor, Trichostatin A, genes nearby this latter class of enhancers are up-regulated, demonstrating the potential for endogenous functionality of these regulatory elements. In conclusion, WHG-STARR-seq provides an improved approach to current pipelines for analysis of high complexity genomes to gain a better understanding of the intricacies of transcriptional regulation.},
doi = {10.1186/s13059-017-1345-5},
journal = {Genome Biology (Online)},
number = 1,
volume = 18,
place = {United States},
year = {2017},
month = {11}
}

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